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1616 Part XI: Malignant Lymphoid Diseases Chapter 97: Hodgkin Lymphoma 1617

NODULAR LYMPHOCYTE PREDOMINANT mortality but disease recurrence continues to present a major challenge,
HODGKIN LYMPHOMA with failure-free survivals in the 20 to 30 percent range. 199–201
As mentioned above, the anti-CD20 antibody rituximab achieves
NLPHL presents as asymptomatic, limited-stage disease in most (~80 high response rates in relapsed NLPHL and can be used as retreat-
percent) patients. 103,104,109 Peripheral lymph nodes in the neck, axilla, or ment or as an extended-treatment regimen. 189,202 Monoclonal anti-
groin are commonly involved as stage IA disease. The European Task bodies directed against the CD30 antigen are well tolerated in classical
Force on lymphoma reported a 96 percent complete response rate and Hodgkin lymphoma but have limited therapeutic value. However,
203
99 percent and 94 percent 8-year disease-specific survival for stages I the anti-CD30 antibody–drug conjugate, brentuximab vedotin has
109
and II disease, respectively. Because of the low likelihood of occult major activity with 96 of 102 patients with relapsed or refractory cHL
disease in nodular lymphocyte-predominant Hodgkin lymphoma and experiencing tumor shrinkage in a phase II clinical trial, including 75
the tendency for the disease to remain localized for years, regional percent with objective remissions and 34 percent with complete remis-
radiation therapy is considered the treatment of choice for early stage sions. The agent has also shown major efficacy when used as a bridge to
183
disease. Analyses from the GHSG demonstrate that outcomes with allogeneic transplantation or in patients relapsing after allogeneic stem
104
204
limited radiation therapy are comparable to the use of more extensive cell transplantation. The major toxicity of this agent when used as a sin-
205
radiation and combined modality regimens. For the 20 percent of gle agent is peripheral neuropathy, though mild to moderate cytopenias
187
patients who present with stage III or IV disease, most authorities advise also occur. Nivolumab and pembrolizumab are PD-1 blocking antibodies
treatment with ABVD-based chemotherapy following the paradigms that have recently been shown to have remarkable efficacy in patients with
104
developed for cHL, although some contend that alkylator-based regi- relapsed or refractory cHL, with objective remission rates of up to 87 per-
mens such as rituximab, cyclophosphamide, hydroxydaunorubicin, vin- cent observed in trials enrolling heavily pretreated patients. 205A
cristine (Oncovin), prednisone (R-CHOP) may be equally effective and
188
less toxic. Because of the consistent high level expression of the CD20
antigen on the surface of NLPHL cells, the monoclonal antibody ritux- COURSE AND PROGNOSIS
imab has been tested in this entity. Initial studies were conducted using
single-agent rituximab in relapsed and refractory cases and demon- The goal of treatment for Hodgkin lymphoma is to cure the greatest
strated response rates of 94 to 100 percent with median durations of number of patients with the fewest complications. Improvements
remission of 33 to 60 months, with longer remissions observed when in management have resulted in cure for a large majority of patients
maintenance rituximab was used. 189,190 Based on these findings,, and the younger than age 65 years. Survival expectations at 10 years for patients
low toxicity of rituximab, some authorities have extrapolated its use to diagnosed from 2006 to 2010 exceed 90 percent for patients to age
the frontline setting, adding it to radiotherapy for stage I or II patients 44 years, 80 percent for patients to age 54 years, and 70 percent for
188
206
and to ABVD for stage III or IV disease, although few data been pub- patients to age 64 years. These outstanding results have been achieved
lished concerning the frontline use of this agent in NLPHL. by refining the use of radiotherapy and chemotherapy in the frontline
setting and the development of improved secondary treatments for
patients with persistent or relapsed disease. However, the late effects of
RECURRENT DISEASE treatment for Hodgkin lymphoma remain a concern for cured patients,
Historically, patients with cHL who relapsed after a full course of che- and a small subset of patients has refractory disease.
motherapy had a low chance for cure with second-line treatment, with
the duration of initial remission a significant predictor of subsequent
response and relapse-free survival. High-dose therapy and autologous CLINICAL PROGNOSTIC FACTORS
blood stem cell transplantation improved the outlook for such patients A number of complex prognostic factor schemes have been developed
and is routinely employed in first relapse for most patients younger than for limited Hodgkin lymphoma treated with radiotherapy alone (see
age 65 years, based on institutional and phase III trial experience. 191,192 Table 97–4). Massive mediastinal disease and constitutional symptoms
Cure rates with transplantation range from 40 to 60 percent with trans- have been consistently identified as independent predictors of relapse,
plant-related mortality less than 5 percent. 193,194 High-dose regimens whereas only older age was predictive of inferior survival. European and
include BEAM (carmustine, etoposide, cytarabine, melphalan), CBV Canadian investigators incorporated gender, age, ESR, number of Ann
(cyclophosphamide, carmustine, etoposide), and total-body irradiation Arbor disease sites, stage, and histology into stratifications for favorable,
with cyclophosphamide and etoposide. Consolidation radiotherapy is very favorable, and unfavorable disease categories. The EORTC defines
often employed to sites of pretransplantation bulk disease. The superi- four or more nodal sites, ESR greater than 50 in asymptomatic patients
ority of any single transplant conditioning regimen has not been defin- or ESR greater than 40 in symptomatic patients, and histology as indi-
itively established; however, the use of high-dose sequential therapy cators of intermediate disease, whereas the GHSG designates any one
coupled with tandem autologous transplantation is being tested in ran- of the following: massive mediastinal disease, extranodal disease, ESR
domized trials. 195,196 In most cases, second-line chemotherapy with ICE greater than 50 if asymptomatic and greater than 30 if symptomatic,
(ifosfamide, carboplatin, etoposide), GVD (gemcitabine, vinorelbine, and three or more nodal sites as intermediate disease (see Table 97–4).
liposomal doxorubicin), DHAP (dexamethasone, cytarabine, cisplatin), It is important to be aware of the variable eligibility criteria when inter-
or brentuximab vedotin is used to achieve a minimal disease state prior preting the literature in early stage Hodgkin lymphoma and to note that
to stem cell mobilization and transplantation. 197–199 Treatment failures these clinical variables are currently used to group patients for clini-
following autologous transplantation present a challenge, with longevity cal investigations. The international prognostic score, based on seven
directly related to the time to relapse after transplantation. Allogeneic factors (see Table 97–4), is used in advanced disease. 124,207 Each factor
transplantation in multiply recurrent Hodgkin lymphoma has been lim- reduced the freedom from progression by approximately 7 percent.
ited by significant transplant-related mortality, although long-term dis- Only 7 percent of patients were in the worst prognostic group (five to
ease control has been observed in a small subset together with anecdotal seven factors) and the freedom from progression in this subset was
evidence of a graft-versus-Hodgkin antitumor effect. Nonmyeloabla- 42 percent at 5 years. Consensus with regard to prognostic factors pro-
tive transplantation conditioning regimens reduce transplant-related motes uniformity in clinical trial design and provides a rationale for

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